This is a new R01 application to continue and extend research begun with support from a cooperative agreement (U-19) with NIDA under its Strategic Program for Innovative Research on Cocaine Addiction Pharmacotherapy (SPIRCAP). Kappa opioids may act as functional antagonists of cocaine, and we have found that kappa opioids with mixed activity at both kappa and mu receptors decrease cocaine self-administration more effectively and with fewer side effects than highly selective kappa opioids. We now propose to test the hypothesis that mu opioid activity is important for optimal anti-cocaine effects of kappa opioid agonists by synthesizing opioids with full kappa agonist activity and systematically varying the degree of efficacy at the mu receptor. A second goal is to increase the duration of pharmacologic action, because kappa opioids are usually very short acting. A third goal is to decrease the toxic effects sometimes seen after acute kappa opioid administration. The resulting novel mixed kappa/mu opioids should have a significantly better pharmacodynamic and pharmacokinetic profile than kappa opioids currently available. On the basis of our preclinical findings, we now propose to synthesize cyclorphan and novel N-alkyl analogs; 10-keto-morphinan derivatives; 6-oxa- and 8-oxamorphinans; aminothiazole analogues of morphinans and ethylketocyclazocine (EKC). Within each series, approximately 10 compounds that vary with respect to their N-alkyl substituents will be synthesized. Each compound will be evaluated for in vitro affinity and selectivity for kappa, mu and delta receptors using guinea pig brain membranes and/or stably transfected CHO cells. Compounds with Ki values < 5 nM at kappa receptors will be further evaluated for agonist/antagonist efficacy at mu, kappa and delta receptors using [35S]GTPgammaS binding assays. Antinociceptive properties of novel kappa opioids will be studied in mice using an acetic-acid writhing test and a tail flick assay. The [35S]GTPgammaS binding assay will give an in vitro determination of efficacy and the antinociceptive tests will yield an in vivo determination of efficacy. The goal of these studies is to obtain compounds that are kappa agonists with varying degrees of agonist and antagonist activity at the mu receptor. These two measurements of efficacy will allow us to develop pharmacological profiles of the compounds that may allow us to predict which compounds will be effective in reducing cocaine self-administration. Compounds with the desired pharmacological profiles will be tested in monkeys at the McLean Hospital Alcohol and Drug Abuse Research Center, but support for these studies is not requested in this application. Kappa opioid synthesis will be carried out at the Alcohol and Drug Abuse Research Center, McLean Hospital, under the direction of John L. Neumeyer, Ph.D. Novel compound in vivo and in vitro evaluations will be conducted by Jean M. Bidlack, Ph.D., in the Department of Pharmacology and Physiology at the University of Rochester under, a consortium arrangement.